In this project we seek to understand how alterations in the oral and gut microbial flora might contribute to the pathogenesis of lgG4-related disease. Recent studies on this disease and the dominance of clonal interferon gamma expressing helper T cells suggests broad similarities to Crohn's disease as well as to mycobacterial diseases, disorders in which the role of microbes in not in question. The presence of a unique polarized T cell population also suggests the potential involvement of specific intestinal microbial species or communities in the disease process. There is a strong case to be made therefore to look at the microbiome in lgG4-related disease. There are three aspects to these studies. In one aspect we will directly examine tissue samples from diseased organs for the presence of microbial components using Next Generation Sequencing approaches. We will also look at the oral microbial flora comparing patients with salivary gland and palatal disease with those in which these organs are not involved and also segregate patients based on clinical and immunological characteristics and genetic differences. We will also examine the intestinal microbial flora in subjects with different clinical, immunological and genetically distinct disease subtypes for distinct bacterial community memberships to see whether community memberships contribute to disease or are potentially altered by the disease process. We will monitor changes in community memberships after treatment to attempt to answer this issue. Finally we will ask if defined subgroups of subjects with lgG4-RD have differences in terms of the metagenome or the metatranscriptome.